Magnetic resonance imaging (MRI) is a medical imaging technique used to obtain anatomical, physiological and biochemical information based on relaxation of proton spin in a magnetic field. It is one of excellent imaging techniques capable of visualizing the body organs of a human or an animal in real time in a non-invasive manner.
In the field of bioscience and medicine, a substance is injected from outside to enhance contrast in MRI. This substance is called a contrast agent. On an MRI image, the contrast between tissues occurs because relaxation whereby the nuclear spin of water molecules in a tissue returns to the equilibrium state is different from tissue to tissue. The contrast agent affects the relaxation, thereby altering the relaxation times in different tissues, and induces the change in MRI signals, thereby enhancing contrast between tissues. There occurs difference in precision depending on the feature and function of the contrast agent and the subject to which it is injected. The contrast enhanced using the contrast agent allows more clear imaging by intensifying or weakening image signals from tissues of a particular organ. A contrast agent which intensifies image signals from the MRI target is called a ‘positive contrast agent’ and one which weakens the signals relative to the surroundings is called a ‘negative contrast agent’.
The contrast agents approved for use in human for MRI include ionic Gd(III) complexes such as diethylentriamine-N,N,N′,N″,N″-pentaacetate and (N-Me-glucamine)2[Gd(DTPA)(H2O)] (Magnevist, Schering) exhibiting a magnetic relaxation rate of about 4.7 mM−1s−1 (20 MHz, 298 K) and neutral Gd(III) complexes such as [Gd(DTPA-bismethylamide)(H2O)] (Omniscan, Nycomed) exhibiting a magnetic relaxation rate of about 4.4 mM−1s−1 (20 MHz, 298 K).
The properties required for the MRI contrast agent include thermodynamic stability, water solubility and multidentate structure that allows formation of paramagnetic Gd(III) ions, i.e. high water relaxivity. In addition, the MRI contrast agent should be chemically inert, have low cytotoxicity in vivo and be completely excreted after diagnostic examination.
However, the above contrast agents have relatively low water solubility and magnetic relaxation rate and is relatively highly cytotoxic in vivo. Accordingly, there is a strong need for the development of an optimized MRI contrast agent.
The inventors of the present invention have studied to solve the above-described problems. As a result, they have found that a gadolinium complex comprising a DO3A-tranexamic acid or its ester compound synthesized according to the present invention has bifunctionality of liver-specific and blood-pool contrasting effect and exhibits high relaxivity.